(Stroke. 1997;28:1233-1244.)
© 1997 American Heart Association, Inc.
Articles |
Tumor Necrosis Factor-
A Mediator of Focal Ischemic Brain Injury
From the Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, and Department of Neurology, Carmel Medical Center, Haifa, Israel (A.M.).
Correspondence to Frank C. Barone, PhD, Department of Cardiovascular Pharmacology UW2521, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, King of Prussia, PA 19406. E-mail Frank_C_Barone{at}SBPHRD.DOC
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Background and Purpose Tumor necrosis factor-
(TNF-) is
a pleiotropic cytokine that rapidly upregulates in the brain
after injury. The present study was designed to explore the
pathophysiological significance of brain TNF- in
the ischemic brain by systematically evaluating the effects of
lateral cerebroventricular administration of exogenous
TNF- and agents that block the effects of TNF- on focal stroke
and by examining the potential direct toxic effects of TNF- on
cultured neurons to better understand how TNF- might mediate stroke
injury.
Methods TNF- (2.5 or 25 pmol) was administered
intracerebroventricularly to
spontaneously hypertensive rats 24 hours before permanent or transient
(80 minutes and 160 minutes) middle cerebral artery occlusion (MCAO).
Animals were examined 24 hours later for neurological deficits and
ischemic hemisphere necrosis and swelling. In some of these
studies, neutralizing anti–TNF- monoclonal antibody (mAb) (60 pmol)
was injected intracerebroventricularly
30 minutes before exogenous TNF- (25 pmol). In addition, the effects
of blocking endogenous TNF- on permanent focal
ischemic injury were determined with the use of either mAb (60
pmol) or soluble TNF receptor I (sTNF-RI) (0.3 or 0.7 nmol)
administered intracerebroventricularly
30 minutes before and 3 and 6 hours after MCAO. Finally, the direct
neurotoxic effects of TNF- were studied in cultured rat cerebellar
granule cells exposed to TNF- (10 to 2000 U/mL for 6 to 24 hours),
and neurotransmitter release, glutamate toxicity, and oxygen radical
toxicity were studied.
Results TNF- increased the percent hemispheric infarct
induced by permanent MCAO in a dose-related manner from 13.1±1.3%
(vehicle) to 18.9±1.7% at 2.5 pmol (P<.05) and
27.1±1.3% at 25 pmol (P<.0001). The high dose of TNF-
increased ischemia-induced forelimb deficits from 1.6±0.2 to
2.3±0.2 (P<.01). TNF- (2.5 pmol) also increased the
infarction induced by 80 or 160 minutes of transient MCAO from
1.9±0.9% to 4.3±0.4% (P<.01) and from 14.2±1.3% to
21.6±2.2% (P<.05), respectively. The exacerbation of
infarct size, swelling, and neurological deficit after exogenous
TNF- was reversed by preinjection of 60 pmol mAb. Blocking
endogenous TNF- also significantly reduced focal
ischemic brain injury. Treatment with 60 pmol mAb before and
after permanent MCAO significantly reduced infarct size compared with
control (nonimmune) antibody treatment by 20.2% (P<.05).
Reduced brain infarction also was produced by brain administration of
0.3 nmol (decreased 18.2%) or 0.7 nmol (decreased 26.1%;
P<.05) sTNF-RI before and after focal stroke. The
intracerebroventricular administration
of TNF- or sTNF-RI did not alter brain or body temperature, blood
gases or pH, blood pressure, blood glucose, or general blood chemistry.
In cultured cerebellar granule cells, the application of TNF- did
not directly affect neurotransmitter release or glutamate or oxygen
free radical toxicity.
Conclusions These studies demonstrate that exogenous
TNF- exacerbates focal ischemic injury and that blocking
endogenous TNF- is neuroprotective. The specificity of
the action(s) of TNF- was demonstrated by antagonism of its effects
with specific anti–TNF- tools (ie, mAb and sTNF-RI). TNF-
toxicity does not appear to be due to a direct effect on neurons or
modulation of neuronal sensitivity to glutamate or oxygen radicals and
apparently is mediated through nonneuronal cells. These data suggest
that inhibiting TNF- may represent a novel pharmacological
strategy to treat ischemic stroke.
Key Words: cerebral ischemia • middle cerebral artery occlusion • neuroprotection • tumor necrosis factor • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tumor necrosis factor-
is a pleiotropic cytokine and appears to be involved
in blood-brain barrier, inflammatory, thrombogenic, and vascular
changes associated with brain injury (for reviews, see References 1
through 31 2 3 ). TNF- levels in brain tissue, cerebrospinal fluid, and
plasma have been found to be elevated in several central nervous system disorders, including
Alzheimer's disease,4 multiple
sclerosis,5 Parkinson's disease,6
meningococcal meningitis,7 and HIV
infection.8 The major cellular elements capable of TNF-
production in the brain have been identified in many different
cell types after various types of stimulation/injury, including
ependymal cells of the choroid plexus,9 activated
astrocytes and microglia,10 11 12 and microglia and
macrophages after ischemia13 14 15 as well as
in central neurons after lipopolysaccharide
treatment,16 cerebral focal
ischemia,13 and brain injury.17
We previously demonstrated that early, increased neuronal expression of
TNF- mRNA in the rat ischemic cortex preceded the leukocyte
infiltration that occurs after focal stroke.13 18 19
Recently, early TNF- mRNA and protein expression were identified in
microglia and activated macrophages after
ischemia in the rat14 and mouse15
brain. The direct administration of TNF- into the brain produces a
dramatic increase in leukocyte adhesion to vascular walls and an
infiltration of these inflammatory cells into tissue but no direct
neurotoxicity to neurons at the site of injection.13
Based on the available data, we hypothesized that applying TNF-
directly to the brain would exacerbate the degree of injury after
cerebral ischemia. In addition, to test the hypothesis that
endogenous TNF- is an important mediator of focal
ischemic injury, we used two different but specific methods of
blocking TNF- during ischemia: an anti–TNF- monoclonal
antibody (mAb) and a soluble TNF receptor. Finally, based on these
earlier studies we hypothesized that the effects of TNF- on
ischemic injury may not be due to its direct effects on
neurons. Therefore, the aims of the present series of experiments
were (1) to determine the effects of TNF-, preadministered into the
brain cerebroventricular system, on the degree of brain
injury and neurological deficits after focal stroke; (2) to determine
the neuroprotective effects of blocking TNF- with the use of a
specific antibody and a soluble receptor to TNF-; and (3) to study
the direct effects of TNF- on cultured neurons to begin to evaluate
potential mechanisms for TNF- in the mediation of ischemic
brain injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Focal ischemia experiments were performed on male SHR (Taconic Farms, Germantown, NY) (weight range, 280 to 340 g). SHR were chosen because they exhibit a more consistent degree of damage after permanent or transient focal ischemia than normotensive rats.20 Body temperature was maintained at 37°C during all surgical procedures and during recovery from anesthesia (ie, until normal locomotor activity was observed). For primary neuronal cell culture experiments, 8-day-old Sprague-Dawley rat pups (Taconic Farms) were used.
Animals were housed and cared for in accordance with the Guide for the Care and Use of Laboratory Animals (Bethesda, Md: Office of Science and Health Reports, DRR/NIH; 1985. US Dept of Health, Education, and Welfare [Dept of Health and Human Services] publication 85-23). Procedures in which laboratory animals were used were approved by the Institutional Animal Care and Use Committee of SmithKline Beecham Pharmaceuticals.
Effects of Brain TNF- Administration on Focal Ischemia
A study to evaluate the effects of brain TNF- pretreatment on
focal stroke injury was executed during a 3-day period. On day 1 the
animals were anesthetized with isoflurane (4% for induction
and 2% for maintenance) and placed in a small-animal
stereotaxic frame (David Kopf Instruments) for ICV
injections. A sterile stainless steel cannula (OD=0.4 mm) was
inserted into the left lateral ventricle through a small hole drilled
in the skull (AP=0.2, L=1.5 from bregma, and V=3.2 from the dural
surface with the skull level). A 5-µL solution of either TNF- (50
ng as 2.5 pmol or 500 ng as 25 pmol) or the vehicle (sterile PBS,
containing 0.1% BSA) was infused into the ventricle with a
microinfusion pump (Harvard Apparatus 22) over 20 minutes.
The cannula was left in place for an additional 5 minutes to allow full
absorption of the solution into the ventricle. In some groups 25
minutes before the left ventricular infusion of TNF- or
the PBS vehicle, a 5-µL solution of anti–TNF- monoclonal antibody
(mAb) (10 µg or 
60 pmol), purified IgG antibody (IgG) (10 µg or
60 pmol as a nonimmune antibody control), or vehicle (PBS) was
injected into the right ventricle. The recombinant mouse TNF- and
monoclonal hamster anti-murine TNF- were obtained from Genzyme
Diagnostics, and purified hamster IgG was obtained from
Rockland Inc. On day 2 (24 hours after these ICV injections), the
animals were anesthetized with pentobarbital (65 mg/kg IP) and
underwent permanent MCAO for 24 hours or transient (80 or 160 minutes)
MCAO followed by 24 hours of reperfusion, as described
previously.19 20 21 Sham surgery was produced in some
animals, also as described previously.18 19 20 On day 3 (24
hours after permanent MCAO or after 24 hours of reperfusion following
transient MCAO), each rat was evaluated for neurological deficits with
a graded scoring system, as previously described.22 In
this scale, grade 1 denotes any amount of consistent
contralateral forelimb flexion, grade 2 denotes grade 1 plus reduced
resistance to lateral shift toward the contralateral side, and grade 3
denotes grade 2 deficits plus circling behavior toward the paretic
side. Grade 0 was assigned to animals with no consistent
deficits. Rats were then killed by an overdose of sodium pentobarbital
(100 mg/kg IP). The brains were immediately removed, and 2-mm coronal
sections were cut from the entire forebrain area (ie, from the
olfactory bulbs to the cortical-cerebellar junction) with a brain
slicer (Zivic-Miller Laboratories). The coronal sections were
immediately stained in a solution of 1%
triphenyltetrazolium chloride, as described
previously.23 Sections were transferred to 10% formalin
(in 0.1% sodium phosphate buffer) for at least 24 hours and then
photographed and analyzed with the use of an image
analysis system, as described previously.20 21
Infarct size was expressed as the percent infarcted tissue in reference
to the contralateral hemisphere, and hemispheric swelling was expressed
as the percent increase in the size of the ipsilateral hemisphere
compared with the contralateral hemisphere. Infarct volume (in cubic
millimeters) was also determined for each animal.
Effects of Blocking Brain TNF- on Focal Ischemia
Endogenous (central) TNF- was blocked before and
during focal stroke by repeated ICV administrations of mAb or sTNF-RI.
These studies were conducted over a 3-day period. On day 1, animals
were anesthetized with pentobarbital, and a stainless steel
guide cannula (OD=1.0 mm) was cemented in place at the same
stereotaxic coordinates as described above, except that
D=2.7 from the dural surface (ie, located just over but not penetrating
the right lateral ventricle). On day 2, 5 µL containing appropriate
control solution/vehicles, 10 µg (60 pmol) mAb, and 5 µg (0.3
nmol) or 12.5 µg (0.7 nmol) sTNF-RI was administered over a
2-minute period at 30 minutes before and 3 and 6 hours after permanent
MCAO with the use of a cannula (OD=0.4 mm) that just penetrated
the ventricle when positioned into the guide cannula. Control solution
for mAb was 10 µg (60 pmol) nonimmune IgG. The vehicle for sTNF-RI
was PBS containing 0.1% BSA. The sources for mAb and IgG were as
described above. The source for recombinant human sTNF-RI was R&D
Systems. On day 3 (24 hours after permanent MCAO), each rat was
evaluated for neurological deficits and then killed, the brain was
removed, and the forebrain was stained and analyzed as
described above.
TNF- and sTNF-RI Effects on Physiological Measures
To determine whether more nonspecific central effects of TNF-
or its blockade were associated with observed changes in brain injury,
we evaluated the effects of ICV TNF- and sTNF-RI on several relevant
physiological measures. SHR were instrumented for
ICV administration (as described above) and for conscious
recording of blood pressure, as described
previously.20 Rats were then anesthetized and
received 25 pmol TNF-, 0.7 nmol sTNF-RI, or vehicle (PBS) as
described above. Temporalis muscle (as an indirect index of brain
temperature24 ) and rectal (body) temperatures were
measured as described previously25 before ICV treatment
and during 3 hours after ICV treatment (under anesthesia)
and 24 hours later (in conscious animals). In addition, heparinized
blood samples and mean arterial blood pressure data
(averaged from 5-minute intervals) were collected from each of the
instrumented animals over similar time periods. Blood samples were
evaluated with an automated blood gas analyzer (Radiometry) for
PO2, PCO2, and pH.
Blood glucose and general blood chemistry (including sodium, potassium,
calcium, albumin, creatinine, and liver enzymes)
were also determined (Monarch 2000; Instrumentation Laboratory).
TNF- Effects on Cerebellar Neurons
Viability, transmitter release, and glutamate and oxygen free
radical toxicity were evaluated in primary cultures of rat cerebellar
neurons26 prepared in groups of 20 cerebellums from the
rat pups and used after 8 to 9 days in culture. Mixed cultures with
astrocytes were obtained by withholding the mitotic
inhibitor cytosine
ß-D-arabinofuranoside. Cells were washed and incubated in
a buffer composed of the following (mmol/L): NaCl 154, KCl 5.6,
CaCl2 2.3, MgCl2 1.0, and HEPES 8.6 adjusted to
pH 7.4 with NaOH. We have previously characterized the pharmacology of
the N-methyl-D-aspartate response in these
neurons, which offer a glutamate excitotoxicity model that is dependent
on compromised energy levels and relief of the voltage-dependent
Mg2+ block.26 27 Neurons
(3x106) in 35-mm dishes were incubated at 37°C in the
above buffer for 40 minutes before the addition of glutamate. The
process consisted of a wash, 10-minute preincubation, and 30-minute
incubation, each in 1 mL of fresh buffer. Recombinant mouse TNF- and
IL-1ß (Genzyme Diagnostics) were added in increasing
concentrations to the growth medium as a sensitizing pretreatment, 6 or
24 hours before the experiments, and were subsequently removed with the
washes. Thirty minutes after glutamate addition, cells were assessed
for viability by staining with fluorescein diacetate
(Sigma), which had been freshly diluted 1:1000 into incubation buffer
from a stock of 10 mg/mL acetone. The staining solution (1 mL) was
aspirated after 5 minutes and replaced with fresh buffer containing
glucose for immediate counting of viable neurons by
fluorescence microscopy. Viability was expressed as a
percentage of the total number of cells retaining
fluorescein. Toxicity data are averaged duplicate
determinations from separate titrations from three different neuronal
preparations that were prepared on separate days.
We also determined the effect of TNF- on delayed glutamate
neurotoxicity 24 hours after glutamate administration (ie, a time that
more closely mimics the in vivo time course associated with
ischemic stroke toxicity) and following the procedure of Manev
et el.28 Neurons were treated overnight with up to 50 000
U/mL TNF-, the growth medium was removed, and cells were washed in
the same buffer as above but containing 5.6 mmol/L glucose and
lacking MgCl2. Neurons were then exposed to increasing
concentrations (10 µmol/L to 1 mmol/L) of glutamate for 5
minutes at room temperature and washed once in fresh complete buffer,
the growth medium containing TNF- was replaced, and neurons were
scored for toxicity after 24 hours.
For neurotransmitter release experiments, neurons in 35-mm dishes were
washed and incubated in 1 mL buffer with 1 µCi
D-[2,3-3H]aspartic acid (NET-581, DuPont NEN
Research Products) for 15 minutes at 37°C, as previously
described.29 30 Labeled neurons were rapidly washed twice
in buffer and incubated with 1 mL buffer that was sequentially removed
and replaced every 4 minutes (4 times over 16 minutes). Veratridine or
KCl was then added to induce efflux and maintained throughout for 24
minutes, with six replacements at 4-minute intervals. Experiments were
terminated by adding 500 µL (twice) of 0.1% NaOH to solubilize
cells, and radioactivity was determined along with the buffer samples
by liquid scintillation counting in 10 mL Ready Safe (Beckman
Instruments). Rate constants (k) for [3H]aspartate efflux
at each time interval were calculated according to the following
equation:
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and IL-1ß
were added in increasing concentrations to the growth medium in
separate dishes 6 or 24 hours before the [3H]aspartate
efflux experiments.
For the oxygen free radical experiments, cerebellar granule cell
cultures grown in 35-mm dishes were deprived of glucose for 40 minutes
before being exposed to a free radical–generating system
(DHF-Fe3+/ADP) composed of final concentrations (mmol/L) of
DHF 0.83, FeCl3 0.025, and ADP 0.25, which generates
superoxide anions and hydroxyl radicals.31 SB 211475 is a
potent metabolite of carvedilol and was added to neurons in the
glucose-free buffer described above 20 minutes before addition of the
free radical–generating system, as described
previously.32 TNF- was added to the growth medium 6
hours before the experiments. After neurons were exposed to the
DHF-Fe3+/ADP for 20 minutes, the free radical–generating
system was removed and replaced with glucose-free buffer. Toxicity was
assessed 50 to 60 minutes later by staining with
fluorescein diacetate, as previously
described.31 32 Protection of neurons was determined by
counting cells and expressing the percent viability.
Statistical Analysis
Results are presented as mean±SE. Statistical
analyses of all data were performed with the use of ANOVA with
Dunnett or Tukey follow-up tests or t test if appropriate.
Significance was accepted at P<.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF-
Exacerbates Stroke InjuryAnimals injected ICV with vehicle 24 hours before MCAO exhibited a 13.1±1.3% hemispheric infarct. Injection of 2.5 pmol TNF-
24 hours
before the permanent MCAO produced a significant (P<.05)
increase in the infarct size to 18.9±1.7%. Injection of 25 pmol
TNF- produced an even greater (P<.01) increase in the
infarct size to 27.1±1.3% (Fig 1A
). In
vehicle-injected animals there was a 4.6±0.7% increase in the
ipsilateral hemispheric size (swelling). In the 2.5-pmol TNF- group
there was a significant (P<.05) augmentation in swelling
(up to 9.8%±1.6%) compared with the vehicle-injected animals. There
was no significant increase in swelling in the group injected with 25
pmol TNF-. The neurological score for the sham-operated animals was
0±0 (n=4). In the vehicle-injected group the neurological score was
1.6±0.2. There was a significant increase in the score for the 25-pmol
TNF- group (up to 2.3±0.2; P<.05) and a small,
nonsignificant increase in the 2.5-pmol TNF- group (up to 1.7±0.2)
(Fig 1B).
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In the animals undergoing 80 minutes of MCAO with reperfusion, 2.5 pmol
TNF- produced a significant (P<.05) increase in infarct
size (4.3±0.4%) compared with the animals receiving vehicle
(1.9±0.9%) (Fig 2). There was no significant increase
in swelling in this group of animals, and only small variable
neurological deficits were observed (data not shown). In the animals
undergoing 160 minutes of MCAO with reperfusion, 2.5 pmol TNF-
also produced a significant (P<.05) increase in infarct
size (21.6±2.2%) compared with the animals receiving vehicle
(14.2±1.3%) (Fig 2). There was no significant difference in swelling
between the groups receiving vehicle (3.2±1.7%) or 2.5 pmol TNF-
(2.7±0.8). There was a small, nonsignificant increase in the
neurological score in the 2.5-pmol TNF- group (1.2±0.4) compared
with the vehicle group (0.8±0.2).
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Vehicle-injected (ie, PBS into both right and left ventricles) rats
that received permanent MCAO exhibited a 19.5±0.9% hemispheric
infarct. Injection of exogenous (25 pmol) TNF- into the left
ventricle (after PBS vehicle injection into the right ventricle)
significantly (P<.05) increased infarct size to 29.2±0.9%
(Fig 3A). Preinjection of 60 pmol TNF- mAb into the
right ventricle 30 minutes before exogenous (25 pmol) TNF- into the
left ventricle significantly (P<.0001) reduced the
exacerbation observed with this dose of TNF- (ie, decreased to
21.5±0.9%). There was no significant difference in infarct size
between the animals receiving mAb plus PBS injections compared with
animals receiving bilateral PBS injections (Fig 3A), indicating that a
single pretreatment with mAb was not sufficient to reduce
ischemic injury due to endogenous TNF-. The
percent hemispheric infarct in the animals receiving 60 pmol purified
hamster IgG in the right ventricle plus 25 pmol TNF- in the left
ventricle (29.3±3.7%) was not significantly different from that in
the group receiving PBS in the right ventricle plus 25 pmol TNF- in
the left ventricle.
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Permanent MCAO in bilateral PBS-injected animals produced a 3.8±1.4%
increase in hemispheric swelling (Fig 3B
). Injection of 25 pmol TNF-
into the left ventricle (before PBS injection into the right ventricle)
significantly (P<.05) increased swelling to 9.2±0.9%.
Preinjection of 60 pmol mAb into the right ventricle 30 minutes before
25 pmol TNF- into the left ventricle significantly
(P<.05) reduced the exacerbation in swelling observed with
25 pmol TNF- (ie, down to 2.2±0.7%). There was no significant
difference in tissue swelling between animals receiving mAb plus PBS,
animals receiving mAb plus TNF-, or animals receiving bilateral PBS
injections. Hemispheric swelling in the animals receiving nonimmune IgG
into the right ventricle plus TNF- into the left ventricle
(9.7±1.9%) was not significantly different from the group receiving
PBS into the right ventricle plus 25 pmol TNF- into the left
ventricle. In all studies, changes in infarct volume were identical to
those that occurred in percent hemispheric infarct size (data not
shown).
Neurological grade for the rats injected bilaterally with PBS
undergoing permanent MCAO was 1.6±0.2 (Fig 3C). Injection of TNF-
into the left ventricle (before PBS injection into the right ventricle)
significantly (P<.05) increased the neurological grade to
2.1±0.1. Preinjection of 1.7 nmol mAb into the right ventricle 30
minutes before TNF- into the left ventricle significantly
(P<.05) reduced the worsening of the neurological score
observed with TNF- (ie, decreased down to 1.5±0.2). There was no
significant difference in the scores between animals receiving TNF-
plus PBS, animals receiving mAb plus TNF-, or animals receiving
bilateral PBS injections. The score in the animals receiving nonimmune
IgG plus TNF- was not significantly different from the group
receiving PBS plus TNF- injections.
Blocking TNF- Reduces Stroke Injury
Based on earlier demonstrations of increased central
neuronal and microglial expression of TNF- after focal
stroke,13 14 15 endogenous (central) TNF- was
blocked before and during focal stroke by repeated ICV administrations
of mAb or sTNF-RI. Treatment before and during 24 hours of focal
ischemia with repeated ICV mAb or sTNF-RI significantly reduced
focal ischemic injury. Fig 4A illustrates the
results on percent hemispheric infarct for 60 pmol mAb compared with
control (equivalent amount of nonimmune IgG) treatment. Identical
results were also observed on infarct volume that also was measured in
the same animals (control=147.2±7.5 mm3 compared with
mAb=117.4±7.0; P<.05). Fig 4B depicts the results on
percent hemispheric infarct for sTNF-RI compared with vehicle (PBS plus
0.1% BSA) treatments. Again, identical results were obtained on
infarct volume measured in the same animals (vehicle=119.5±7.5
mm3; 5 µg or 0.3 nmol sTNF-RI=97.8±8.5
mm3; 12.5 µg or 0.7 nmol sTNF-RI=89.0±7.6
mm3; P<.05). The small degree of percent
hemispheric swelling that occurred under these conditions (2.3±0.5%
to 1.9±0.8%) was not altered by the TNF-–blocking treatments. In
addition, neurological scores (1.9±0.1% to 1.8±0.2%) were not
altered by these treatments.
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Brain TNF- Manipulation Did Not Affect Other Monitored
Physiological Variables
To evaluate potential nonspecific effects of ICV treatments that
may have influenced brain injury, several relevant variables were
monitored. Table 1 lists the effects of ICV vehicle
(PBS), TNF-, and sTNF-RI on temporalis muscle and rectal
temperatures. Table 2 lists the effects of these ICV
treatments on blood pressure. Table 3 lists these
results for blood gases, pH, and glucose. No significant differences
for any measures were observed between ICV treatments. In addition, no
differences due to ICV treatments were observed for any of the other
measurements of blood chemistry (data not shown).
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TNF- Effects on Cerebellar Neurons
To determine whether the increase in ischemia-induced
brain damage in rats pretreated with TNF- was due to direct effects
of TNF- on neurons, we studied the effects of TNF- on cultured
rat cerebellar granule cells grown in the presence or absence of
astrocytes. Isolated neuronal cultures contained 90% to 95% neurons
only. Mixed neuronal cultures contained neurons grown above a monolayer
of astrocytes, similar to that described for cortical cultures.
Pretreatment for 24 hours with increasing concentrations of TNF- did
not result in increased release of neurotransmitter from cultured
neurons. This was true for [3H]aspartate efflux induced
with either 50 mmol/L KCl (Fig 5A) or 40
µmol/L veratridine (Fig 5B). Since IL-1ß is also upregulated in
ischemic stroke,18 33 it could act in concert with
TNF- to sensitize neurons to TNF- actions. Therefore, in a series
of additional experiments, IL-1ß was included at concentrations up to
48 ng/mL, with 100 U/mL TNF- as a 24-hour pretreatment. This also
did not result in increased release of [3H]aspartate
efflux induced with either 50 mmol/L KCl (100.4±8.1%) or 40
µmol/L veratridine (94.1±4.9%) (n=7 for each condition).
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We also studied the effects of TNF- and IL-1ß on glutamate
neurotoxicity in cultured neurons. As seen in Fig 6, 24-hour pretreatment with up to 2000 U/mL TNF- and 100 ng/mL IL-1ß
did not shift the dose response for glutamate excitotoxicity compared
with neurons receiving only glutamate. Also, TNF- or IL-1ß alone
had absolutely no toxic effects on the neurons (ie, >95% viability in
eight separate experiments). Because the above experiments are a model
of acute glutamate toxicity (death in 30 minutes), while MCAO results
are assessed after 24 hours, we also studied glutamate toxicity in
cultured neurons after a delay period (ie, in a 24-hour
model28 ). Pretreatment with from 5000 to 50 000 U/mL
TNF- did not directly injure the cultured neurons, nor did it
significantly shift the dose-response curve for delayed glutamate
toxicity (n=3; data not shown). Therefore, TNF- pretreatment had no
direct effect on either acute or delayed glutamate excitotoxicity in
this well-characterized model system.
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To investigate whether TNF- might act on neurons at an earlier time
point, we performed similar tests after only 6 hours of incubation with
1000 U/mL TNF-. We also compared the effects of TNF- on neurons
grown in the presence of astrocytes, which might have an influence on
neuronal sensitivity/toxicity. As shown in Fig 7A and 7D, there was no increase in sensitivity to glutamate
excitotoxicity with TNF- pretreatment, although higher glutamate
concentrations were necessary to kill neurons in mixed culture.
Incubation with TNF- for 6 hours also did not alter the
veratridine-induced release of [3H]aspartate (Fig 7B and 7E). We also tested the ability of TNF- to alter the protective
effects of a free radical scavenger and thus influence cell damage by
an oxygen free radical–generating system. We have previously shown
that neuronal cell death was complete 50 minutes after a 20-minute
exposure to a DHF-Fe3+/ADP oxygen free radical–generating
system.31 32 Here the inclusion of 1000 U/mL TNF- as a
6-hour pretreatment did not change the protective dose-response curve
for the free radical scavenger SB 211475, which had an EC50
of approximately 300 nmol/L with or without TNF- pretreatment (Fig 7C and 7F).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pretreatment of the brain with exogenous TNF-
exacerbated
infarct size in both transient and permanent focal stroke models but
did not produce nonspecific effects on brain or body temperature, blood
pressure, blood gases or pH, or blood chemistry. The ICV administration
of TNF- was expected to provide brain concentrations of the
cytokine similar to the elevated pathological levels previously
measured in rodents and humans.34 35 A TNF-
dose-related effect was demonstrated after permanent MCAO (2.5 and 25
pmol), and a consistent increase in injury was observed after
MCAO with reperfusion (80 minutes and/or 160 minutes) with 2.5 pmol
TNF. The effect of TNF- was demonstrated to be specific by the
ability of mAb to completely reverse the exacerbation of infarct size,
swelling, and neurological deficit, while the nonimmune IgG antibody
control treatment had no such effect. It is interesting that
pretreatment with a single ICV administration of mAb was not adequate
to reduce ischemic brain injury (ie, that might be attributed
to endogenous TNF-), but this was effectively reduced by
repetitive administrations before and during ischemia (see
below).
The monoclonal hamster anti-murine TNF- effectively neutralizes the
bioactivity of TNF-, has been shown to be specific for (ie,
effectively antagonizes) both mouse and rat TNF-,36 37
and has been demonstrated previously to prevent the transfer of
experimental allergic encephalomyelitis.38 Based on these
studies, the ICV mAb dose used in the present studies was expected
to provide a brain concentration of the antibody that would block
TNF-–mediated effects. Indeed, repeated ICV administrations of mAb
just before and during focal ischemia produced a significant
reduction in ischemic brain injury.
Soluble TNF receptors are truncated forms of the extracellular domains
of the receptors and act as endogenous
inhibitors of TNF- by competing with the cell-surface
receptors for its binding.39 40 sTNF-RI has already
demonstrated efficacy in other brain injury models that are associated
with elevated TNF- levels (eg, brain trauma,41
experimental autoimmune encephalomyelitis,42 43 and lethal
endotoxemia35 ). For example, similar to focal stroke,
brain TNF- levels are increased after head injury,44 45 46
and inhibition of TNF- with sTNF-RI provides
cerebroprotection.41 In the present studies, the
repeated ICV doses of sTNF-RI were used to provide brain concentrations
of the soluble receptor that were expected to block TNF- (ie,
similar to that achieved in other models in which efficacy was
demonstrated35 41 42 43 ). These brain administrations of
sTNF-RI produced a significant decrease in focal stroke injury. In
addition, another laboratory has simultaneously described
neuroprotection due to sTNF-RI administration in focal stroke.
Intravenous sTNF-RI significantly reduces the impairment in
cortical microvascular perfusion that accompanies MCAO and also
decreases the degree of brain injury after MCAO, strongly suggesting a
vascular mechanism for TNF- in stroke.47 In addition,
direct application of sTNF-RI to the ischemic cortex
significantly reduces brain injury in murine MCAO (J.M. Hallenbeck, MD,
personal communication, 1996), thus corroborating the present
results. All these new data support previous reports on TNF- mRNA
and peptide expression in the same stroke model and provide a very
strong case for a role of TNF- as a mediator of ischemic
brain injury.
Hemispheric swelling was evaluated independently for determination of
TNF- treatment effects. Exogenous TNF- pretreatment was able to
exacerbate the small degree of swelling (an index of
edema20 ) that occurs under these conditions. However,
blocking endogenous TNF-, although able to significantly
reduce brain infarction, did not alter swelling. Effects on infarct
size independent of swelling in focal stroke have been observed
previously48 49 and indicate that neuroprotection provided
by blocking endogenous TNF- in the present studies
is not related to the effects of altered swelling and its influence on
the degree of infarction. In addition, although increased neurological
scores related to significantly increased brain infarctions were
observed as a result of TNF- pretreatment, neurological deficits
were not reduced by blocking TNF-, as might be expected from
previous data indicating that larger reductions in infarct size are
necessary to affect this less sensitive measure.48
Although many studies were conducted, we could provide no direct
evidence for TNF- toxicity on neurons in relatively pure or mixed
cultures. Excess glutamate release is known to occur in
ischemic stroke, and the present studies were conducted
with or without glucose in the presence of glutamate (ie, both acute
and delayed standard models of neurotoxicity). In addition, TNF-
together with IL-1ß did not shift the dose response for glutamate
neurotoxicity in these cultured neurons. No augmented release of
[3H]aspartate from the cultured neurons was evident when
TNF- with or without IL-1ß was present in the culture even at
very high concentrations. Similarly, TNF- pretreatment did not
enhance the toxic effects of a free radical–generating system, nor did
it shift the dose-response curve of a protective antioxidant.
Therefore, an indirect augmentation of neuronal damage by TNF- seems
likely. Astrocytes and microglia are the prime brain cell candidates
likely to respond to cytokine stimulation and maintain an
inflammatory response that will ultimately result in long-term neuronal
loss after ischemic stroke. Evidence supporting this
interpretation was recently provided by Chao and Hu,50
using a model system of human fetal neurons cocultivated with
astrocytes, when cultures were exposed to glutamate in the presence of
TNF- for 6 days. Interestingly, IL-1, IL-1ß, transforming
growth factor-ß1, and IL-6 had no effect on glutamate toxicity, while
TNF- augmented glutamate toxicity indirectly by altering glutamate
metabolism in the astrocyte component of the coculture.
TNF- decreased astrocytic glutamine synthetase activity by 27%, as
previously shown in cultured murine astrocytes,51 while
also inhibiting high-affinity glutamate uptake by 50%.50
It is likely that these augmented effects were due to gene induction
over time, since TNF- does induce a p53-dependent
apoptosis in rat glioma cells.52 Such a disruption
in the integrity of support cells could certainly contribute to
increased infarction after MCAO. Our present results, showing no
direct, acute effect of TNF- on pure or mixed neuronal cultures, are
limited in that they are a model system and not identical to the in
vivo situation. However, they do support the possibility that the
effects of TNF- in focal stroke might be due to an augmented
toxicity induced by other cells in the brain after ischemia.
These data are consistent with our earlier work that
illustrated no obvious neuronal damage when TNF- was injected into
the cortex but did show an increase in leukocyte accumulation in blood
vessels at the site of injection.13
Others have also shown that TNF- is not directly toxic to
neurons,53 54 and some investigators even suggest a
protective effect of TNF- on neurons.55 56 57 The broad
scope of the injurious and beneficial effects of TNF- has been
emphasized previously.58 Cytokines have also been
suggested to provide beneficial effects in brain injury, as inferred
from studies with multiple-TNF-receptor knockout mice (p55 and p75
knockout) that display increased sensitivity to brain
ischemia59 60 and the capacity of IL-1 to elicit a
state of ischemic tolerance on repeated
administration.61 We have demonstrated previously the
later expression of TNF- in macrophages involved in
resolution of ischemic brain injury.13 62
Certainly the eventual determination of the role of individual known
and novel TNF receptors will help in our understanding of how to best
target TNF- in tissue injury. Blocking TNF effects, especially at
TNF receptor I, might be expected to block not onlyTNF-mediated
apoptosis but also TNF activation of nuclear factor-
B
(NF-B)–associated inflammation.63 However, the
present data clearly demonstrate that increasing the acute effects
of TNF- is not protective (and in fact increases ischemic
injury) and that blocking the acute increased activity of TNF- that
occurs after focal stroke is neuroprotective.
The toxic effects of TNF- and its role as a mediator of focal
ischemia may involve many mechanisms. For example, TNF-
increases blood-brain barrier permeability and produces pial artery
constriction64 65 that can contribute to focal
ischemic brain injury, and there appears to be a direct toxic
effect of TNF- on the capillary.66 67 TNF- increases
capillary permeability and opens the blood-brain barrier, apparently by
increasing matrix-damaging metalloproteinase (gelatinase B)
production,68 which is also expressed early after
focal stroke.69 TNF- also causes damage to myelin and
oligodendrocytes70 71 and increases astrocytic
proliferation,72 thus potentially contributing to
demyelination and reactive gliosis during brain injury. In addition,
TNF- activates the endothelium for leukocyte
adherence and procoagulation activity (ie, increased tissue factor, von
Willebrand factor, and platelet activating factor) that can
exacerbate ischemic damage.73 Indeed, increased
TNF- in the brain and blood in response to
lipopolysaccharide appears to contribute to increased brain
stem thrombosis and hemorrhage74 75 76 and can
contribute to increased stroke sensitivity/risk in hypertensive
rats.20 Finally, TNF- plays a pivotal role in
inflammatory processes.77 It activates
neutrophils,78 increases
leukocyte–endothelial cell adhesion molecule
expression,73 and increases leukocyte adherence to blood
vessels and their subsequent infiltration into the
brain.13 Clearly, leukocyte transit through capillaries is
impaired after stroke, which contributes to rheological effects due to
microvascular occlusion or plugging.79 80 The efficacy of
neutrophil depletion and the blocking of leukocyte-associated adhesion
molecules has been demonstrated repeatedly (for reviews, see References
1 and 811 81 ). TNF- also stimulates the release of potent vasoactive
agents82 and induces both vasodilation83 and
vasoconstriction and reduced cerebral blood flow,84 thus
modifying blood flow to already ischemic tissue and perhaps
increasing the potential of leukocyte plugging.
The present studies indicate that increasing brain TNF- before
focal stroke can be expected to exacerbate ischemic injury and
that blocking TNF- in a stroke can be expected to reduce focal
ischemic injury. These changes in the degree of
ischemic brain injury do not appear to be related to
nonspecific effects of altering brain TNF-. Clearly, more studies
are necessary to understand the mechanisms for TNF- mediation of
ischemic injury. However, the available data suggest that
blocking this cytokine should be an attractive pharmacological
goal in reducing ischemic injury. Similar to interference with
IL-1 receptors, which reduces brain injury after focal
ischemia85 86 and head injury,87
blocking TNF- has now proven to be protective in focal stroke
(present studies and Reference 4747 ) and head trauma.37
The evaluation of additional potent and specific anti-TNF therapeutics
(see Reference 22 for review) in proper models of stroke is clearly
warranted.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors thank Shirley Wilson and Sue Tirri for assistance in the preparation of this manuscript and Kathy Morasco for performing blood chemistry determinations in the present studies.
|
Footnotes |
|---|
Presented in part at the 21st International Joint Conference on Stroke and Cerebral Circulation, San Antonio, Tex, January 25-27, 1996, and published in abstract form (Stroke. 1996;27:187).
Received September 11, 1996; revision received February 5, 1997; accepted March 12, 1997.
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References |
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